EP0362030B1 - Sel du 6-pipéridino-2,4-diaminopyrimidine-3-oxyde et de l'acide acéturique, sa préparation et son application dermatocosmétologique - Google Patents
Sel du 6-pipéridino-2,4-diaminopyrimidine-3-oxyde et de l'acide acéturique, sa préparation et son application dermatocosmétologique Download PDFInfo
- Publication number
- EP0362030B1 EP0362030B1 EP89402592A EP89402592A EP0362030B1 EP 0362030 B1 EP0362030 B1 EP 0362030B1 EP 89402592 A EP89402592 A EP 89402592A EP 89402592 A EP89402592 A EP 89402592A EP 0362030 B1 EP0362030 B1 EP 0362030B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- minoxidil
- aceturate
- dermatocosmetic
- preparation
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 0 CC(N)=NCC(CC(N)=N*)N1CCCCC1 Chemical compound CC(N)=NCC(CC(N)=N*)N1CCCCC1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
Definitions
- the present invention relates to Minoxidil aceturate, that is to say the salt obtained by salification of Minoxidil, or 6-piperidino-2,4-diamino-pyrimidine-3-oxide, with aceturic acid, or acetyl -glycine, corresponding to formula I
- the object of the present invention also extends to the process for the preparation of Minoxidil aceturate, as well as to its use as an active ingredient in dermatocosmetic compositions, in particular in hair compositions intended for the treatment of alopecia.
- Minoxidil is an antihypertensive compound, well known for its anti-hair loss activity, and as such is used in the treatment of alopecia. Because of its quasi-insolubility in water, it is only used to date in solutions comprising propylene glycol and ethyl alcohol, 50 to 60% by volume for the latter, and therefore irritating for a topical use.
- Minoxidil aceturate has a solubility of 34% W / V at 20 ° C which corresponds to 21.8% of Active minoxidil present in the aqueous solution.
- Minoxidil aceturate can be easily prepared by reacting Minoxidil and aceturic acid, in stoichiometric amounts in an aqueous medium or in an aliphatic alcohol, such as ethanol or isopropanol.
- the salt formed is isolated by precipitation or by crystallization. This synthesis can be carried out according to Examples 1 and 2 below.
- Minoxidil aceturate is a crystalline compound, chemically well defined, very stable, having a melting point close to 155 ° C.
- Minoxidil aceturate is sufficiently dissociable so that the activity of Minoxidil remains unchanged.
- the present invention also relates to the formulations for capillary or pharmaceutical use, containing as active ingredient Minoxidil aceturate.
- the mixture is brought to reflux for 1 hour.
- the hot solution is cooled to 5 ° C.
- aceturic acid 15.2 g of aceturic acid are suspended in 150 ml of water, then 27.2 g of Minoxidil are added with stirring. The crystals dissolve quickly.
- the solution obtained is concentrated to one third of its volume, then 650 ml of isopropanol are added with vigorous stirring. Minoxidil aceturate precipitates quickly.
- Minoxidil aceturate a mixture of 120 ml of distilled water and 30 ml of propylene glycol.
- the dermatocosmetic compositions according to the invention can affect various other forms of presentation, such as shampoos, gels, fixatives or other hair lotions. They have also proved to be very effective in practice for the treatment of allopecic conditions, and in particular have made it possible to eliminate a certain number of harmful side effects, such as irritations of the scalp or weakening of the hair by dehydration, that have been observed in the past when using aqueous solutions of Minoxidil.
- the better bioavailability of the active principle according to the invention makes it possible, with aqueous-based formulations, to lower the concentration of available dissociated Minoxidil. Certain possible toxicity problems are thus perfectly resolved, without reducing the anti-fall activity.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
-
- L'objet de la présente invention s'étend également au procédé de préparation de l'acéturate de Minoxidil, ainsi qu'à son utilisation en tant que principe actif dans des compositions dermatocosmétiques, en particulier dans des compositions capillaires destinées au traitement de l'alopécie.
- Le Minoxidil est un composé antihypertenseur, bien connu pour son activité anti-chute des cheveux, et à ce titre est utilisé dans le traitement de l'alopécie. En raison de sa quasi-insolubilité dans l'eau,il n'est utilisé à ce jour que dans des solutions comprenant du propylène glycol et de l'alcool éthylique, 50 à 60 % en volume pour ce dernier, et donc irritantes pour un usage topique.
- L'intérêt de la présente invention consiste en ce que, contrairement au Minoxidil qui est donc quasiment insoluble dans l'eau et à l'acide acéturique très peu hydrosoluble (2,7 % environ), l'acéturate de Minoxidil présente une solubilité de 34 % P/V à 20°C ce qui correspond à 21,8 % de Minoxidil actif présent dans la solution aqueuse.
- Ainsi, il devient possible de préparer des solutions soit totalement aqueuses, soit contenant des quantités très réduites de propylène glycol favorable à la pénétration du cuir chevelu, mais désormais en absence d'éthanol ou tout autre solvant organique. On évite ainsi tout risque d'irritation cutanée due à la présence de ces solvents.
- L'acéturate de Minoxidil peut être préparé aisément en faisant réagir le Minoxidil et l'acide acéturique, en quantités stoechiométriques en milieu aqueux ou dans un alcool aliphatique, tel que l'éthanol ou l'isopropanol. Le sel formé est isolé par précipitation ou par cristallisation. Cette synthèse peut être réalisée selon les exemples 1 et 2 ci-après.
- L'acéturate de Minoxidil est un composé cristallin, chimiquement bien défini, très stable, ayant un point de fusion voisin de 155°C.
- Comme le montre l'examen chromatographique en solution aqueuse, l'acéturate de Minoxidil est suffisamment dissociable pour que l'activité du Minoxidil reste inchangée.
- La présente invention concerne également les formulations à usage capillaire ou pharmaceutique, contenant comme principe actif l'acéturate de Minoxidil.
- Les exemples 3 et 4 proposent à titre non limitatif deux formulations possibles.
- 20,9 g de Minoxidil et 11,7 g d'acide acéturique sont mis en suspension dans 500 ml d'éthanol.
- Le mélange est porté à reflux pendant 1 heure.
- La solution chaude est refroidie à 5°C.
- Après filtration et séchage, on récupère 29,9 g d'acéturate de Minoxidil, ce qui correspond à un rendement de 92 %. Point de fusion 155°C.
- Les spectre IR et RMN sont conformes à la structure.
- 15,2 g d'acide acéturique sont mis en suspension dans 150 ml d'eau, puis 27,2g de Minoxidil sont ajoutés sous agitation. Les cristaux se dissolvent rapidement.
- La solution obtenue est concentrée au tiers de son volume, puis 650 ml d'isopropanol sont ajoutés sous vive agitation. L'acéturate de Minoxidil précipite rapidement.
- Le mélange refroidi à 5°C est filtré. On récupère ainsi 37,3 g de cristaux blancs, d'acéturate de Minoxidil, ce qui correspond à un rendement de 88 %. Point de fusion : 154-157°C.
- Les spectre IR et RMN sont conformes à la structure.
- 3,12 g d'acéturate de Minoxidil sont dissous dans 100 ml d'eau distillée.
- La solution obtenue, contenant 2 g pour 100 ml de Minoxidil actif est prête pour l'utilisation à usage capillaire.
- 4,68 g d'acéturate de Minoxidil sont dissous dans un mélange de 120 ml d'eau distillée et 30 ml de propylène glycol.
- La solution obtenue contenant l'équivalent de 2 g pour 100 ml de Minoxidil actif, est prête pour l'utilisation à usage capillaire.
- Les compositions dermatocosmétiques selon l'invention peuvent affecter diverses autres formes de présentation, telles que des shampooings, gels, fixateurs ou autres lotions capillaires. Elles se sont en outre avérées très efficaces dans la pratique pour le traitement d'affections allopéciques, et ont notamment permis d'éliminer un certain nombre d'effets secondaires néfastes, tels que des irritations du cuir chevelu ou des fragilisations du cheveu par déshydratation, qui avaient été observées dans le passé lors de l'utilisation de solutions aqueuses de Minoxidil. En outre, la meilleure biodisponibilité du principe actif selon l'invention permet, avec des formulations à base aqueuse, d'abaisser la concentration de Minoxidil dissocié disponible. Certains problèmes éventuels de toxicité se trouvent ainsi parfaitement résolus, sans diminution de l'activité anti-chute.
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT89402592T ATE78154T1 (de) | 1988-09-23 | 1989-09-21 | Salz von 6-(1-piperidinyl-)2,4-diaminopyrimidin-3-oxyd und acetylaminoessigsaeure deren herstellung und deren dermatokosmetische verwendung. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8812442A FR2636840B1 (fr) | 1988-09-23 | 1988-09-23 | Sel du 6-piperidino-2,4-diaminopyrimidine-3-oxyde et de l'acide aceturique, leur preparation et leur application dermatocosmetologiques |
FR8812442 | 1988-09-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0362030A1 EP0362030A1 (fr) | 1990-04-04 |
EP0362030B1 true EP0362030B1 (fr) | 1992-07-15 |
Family
ID=9370311
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP89402592A Expired - Lifetime EP0362030B1 (fr) | 1988-09-23 | 1989-09-21 | Sel du 6-pipéridino-2,4-diaminopyrimidine-3-oxyde et de l'acide acéturique, sa préparation et son application dermatocosmétologique |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0362030B1 (fr) |
AT (1) | ATE78154T1 (fr) |
AU (1) | AU613239B2 (fr) |
CA (1) | CA1323030C (fr) |
DE (1) | DE68902122T2 (fr) |
ES (1) | ES2042033T3 (fr) |
FR (1) | FR2636840B1 (fr) |
GR (1) | GR3005413T3 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8918709D0 (en) * | 1989-08-16 | 1989-09-27 | Unilever Plc | Cosmetic composition |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1020558A (fr) * | 1971-04-07 | 1977-11-08 | Richard C. Thomas (Jr.) | 6-amino-4-(groupement amino substitue)-1,2-dihydro-1-hydroxy-2-iminopyrimidines |
IL78842A0 (en) * | 1985-05-22 | 1986-09-30 | Serono Otc Sa | Piperidino-pyridine derivatives and pharmaceutical and cosmetic compositions containing them |
IT1186772B (it) * | 1985-10-10 | 1987-12-16 | Crinos Industria Farmaco | Composto ad attivita' pilostimolante |
FR2590897B1 (fr) * | 1985-12-06 | 1988-02-19 | Kemyos Bio Medical Research Sr | Nouveaux derives de 6 amino 1,2-dihydro-1-hydroxy-2-imino-pyrimidine, leur procede de preparation et compositions cosmetiques les renfermant |
FI864046A (fi) * | 1986-10-07 | 1988-04-08 | Farmos Oy | Foerfarande foer framstaellning av en terapeutiskt aktiv foerening. |
FI871773A0 (fi) * | 1987-04-22 | 1987-04-22 | Farmos Oy | Foerfarande foer framstaellning av en terapeutiskt aktiv foerening. |
-
1988
- 1988-09-23 FR FR8812442A patent/FR2636840B1/fr not_active Expired - Fee Related
-
1989
- 1989-09-20 CA CA000612139A patent/CA1323030C/fr not_active Expired - Lifetime
- 1989-09-21 AT AT89402592T patent/ATE78154T1/de not_active IP Right Cessation
- 1989-09-21 ES ES198989402592T patent/ES2042033T3/es not_active Expired - Lifetime
- 1989-09-21 EP EP89402592A patent/EP0362030B1/fr not_active Expired - Lifetime
- 1989-09-21 DE DE8989402592T patent/DE68902122T2/de not_active Expired - Lifetime
- 1989-09-25 AU AU41663/89A patent/AU613239B2/en not_active Ceased
-
1992
- 1992-08-11 GR GR920401740T patent/GR3005413T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
AU613239B2 (en) | 1991-07-25 |
FR2636840B1 (fr) | 1990-12-21 |
CA1323030C (fr) | 1993-10-12 |
ES2042033T3 (es) | 1993-12-01 |
EP0362030A1 (fr) | 1990-04-04 |
ATE78154T1 (de) | 1992-08-15 |
AU4166389A (en) | 1990-03-29 |
DE68902122D1 (de) | 1992-08-20 |
GR3005413T3 (fr) | 1993-05-24 |
FR2636840A1 (fr) | 1990-03-30 |
DE68902122T2 (de) | 1992-12-03 |
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